The present invention is directed to benzenamine derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the xe2x80x9cXa burstxe2x80x9d pathway and by the factor IXa-VIIIa complex (TENase) of the xe2x80x9csustained Xaxe2x80x9d pathway in the coagulation cascade. After vessel injury, the xe2x80x9cXa burstxe2x80x9d pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the xe2x80x9csustained Xaxe2x80x9d pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the xe2x80x9cXa burstxe2x80x9d pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique xe2x80x9ctethered ligandxe2x80x9d thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res. (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol.19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of xcex1,xcex1xe2x80x2-bis(amidinobenzylidene)cycloalkanones and xcex1,xcex1xe2x80x2-bis(amidinobenzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
U.S. Pat. No. 5,451,700 (Morrissey et al.) describes amidino compounds. These compounds are stated to be useful as selective LTB4 receptor antagonists.
U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/96/28427 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/96/28427 (Arnaiz et al.) describes naphthyl-substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/29067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,869,501 (Hirayama et al.) describes amidinonaphthyl derivatives and their use as factor Xa inhibitors.
The above references, published patent applications and U.S. patents are herein incorporated in full by reference.
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity.
Accordingly, in one aspect, this invention provides compounds of formula (I): 
wherein:
A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94;
W is xe2x80x94N(R4)xe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94;
each m is independently 0, 1, 2, 3 or 4;
n is 0 or 1;
R1 is hydrogen, alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR8, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), mono[dialkoxycarbonyl]alkylaminocarbonyl, mono[dicarboxy]alkylaminocarbonyl; alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl;
R2 is xe2x80x94[C(R7)2]mxe2x80x94, xe2x80x94[C(R7)2]mxe2x80x94C(O)xe2x80x94N(R8)xe2x80x94, or xe2x80x94[C(R7)2]mxe2x80x94[C(R8)]xe2x95x90CHxe2x80x94; or R2 is 
R3 is xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7;
R4 is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or xe2x80x94C(NH)CH3.
each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl;
R6 is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy);
each R7 and R8 is independently hydrogen, alkyl, aryl, or aralkyl; and
each R9 is alkyl or aralkyl;
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I) as described above.
In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I) as described above.
In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of formula (I).
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
xe2x80x9cAlkylcarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)Ra where Ra is an alkyl radical as defined above, e.g., acetyl, ethylcarbonyl, n-propylcarbonyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORa where Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORa where Ra is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl (iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxycarbonyl, 1,1-dimethylethoxycarbonyl (t-butoxycarbonyl), and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, (n-propoxycarbonylmethyl, 1-methylethoxycarbonylmethyl (iso-propoxycarbonylmethyl), n-butoxycarbonylmethyl, n-pentoxycarbonylmethyl, 1,1-dimethylethoxycarbonylmethyl (t-butoxycarbonylmethyl), and the like.
xe2x80x9cAlkoxycarbonylalkylcarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)RaC(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylcarbonyl, 2-(ethoxycarbonyl)ethylcarbonyl, (n-propoxycarbonylmethylcarbonyl, 1-methylethoxycarbonylmethylcarbonyl (iso-propoxycarbonylmethylcarbonyl), n-butoxycarbonylmethylcarbonyl, n-pentoxycarbonylmethylcarbonyl, 1,1-dimethylethoxycarbonylmethylcarbonyl (t-butoxycarbonylmethyl)carbonyl, and the like.
xe2x80x9cArylxe2x80x9d refers to a phenyl or naphthyl radical.
xe2x80x9cAralkylxe2x80x9d refers to a radical of the formula xe2x80x94RaRb where Ra is an alkyl radical as defined above, substituted by Rb, an aryl radical, as defined above, e.g., benzyl.
xe2x80x9cAralkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORc where Rc is an aralkyl radical as defined above, e.g., benzyloxy, and the like.
xe2x80x9cAmidinoxe2x80x9d refers to the radical xe2x80x94C(NH)NH2.
xe2x80x9cAminocarbonylxe2x80x9d refers to the radical xe2x80x94C(O)NH2.
xe2x80x9cAminosulfonylxe2x80x9d refers to the radical xe2x80x94S(O)2NH2.
xe2x80x9cAminocarbonylalkylxe2x80x9d refers to the radical xe2x80x94RaC(O)NH2, where Ra is an alkyl radical as defined above, e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, and the like.
xe2x80x9cAminocarbonylalkylcarbonylxe2x80x9d refers to the radical xe2x80x94C(O)RaC(O)NH2, where Ra is an alkyl radical as defined above, e.g., aminocarbonylmethylcarbonyl, 2-(aminocarbonyl)ethylcarbonyl, and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d refers to a radical of the formula xe2x80x94S(O)2xe2x80x94Ra where Ra is an alkyl radical as defined above, e.g., methylsulfonyl, ethylsulfonyl, t-butylsulfonyl, and the like.
xe2x80x9cArylsulfonylxe2x80x9d refers to a radical of the formula xe2x80x94S(O)2xe2x80x94Rb where Rb is an aryl radical as defined above, e.g., phenylsulfonyl or naphthylsulfonyl.
xe2x80x9cCarboxyxe2x80x9d refers to the radical xe2x80x94C(O)OH.
xe2x80x9cCarboxyalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)OH, where Ra is an alkyl radical as defined above, e.g., carboxymethyl, 2-(carboxy)ethyl, 3-(carboxy)propyl, and the like.
xe2x80x9cCarboxyalkylcarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)RaC(O)OH, where Ra is an alkyl radical as defined above, e.g., carboxymethylcarbonyl, 2-(carboxy)ethylcarbonyl, 3-(carboxy)propylcarbonyl, and the like.
xe2x80x9cDialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and the like.
xe2x80x9cDialkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl, and the like.
xe2x80x9cDialkylaminosulfonylxe2x80x9d refers to a radical of the formula xe2x80x94S(O)2xe2x80x94N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminosulfonyl, methylethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, ethylpropylaminosulfonyl, and the like.
xe2x80x9cDialkylaminocarbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminocarbonylmethyl, 2-(methylethylaminocarbonyl)ethyl, diethylaminocarbonylmethyl, 3-(dipropylaminocarbonyl)propyl, 4-(ethylpropylaminocarbonyl)butyl, and the like.
xe2x80x9cHaloxe2x80x9d refers to bromo, chloro, iodo or fluoro.
xe2x80x9cHaloalkylxe2x80x9d refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
xe2x80x9cMonoalkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NHRa where Ra is an alkyl radical as defined above, e.g., methylamino, ethylamino, propylamino, and the like.
xe2x80x9cMonoalkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)NHRa where Ra is an alkyl radical as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.
xe2x80x9cMono[dialkoxycarbonyl]alkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(H)[Ra(C(O)ORa)2] where each Ra is independently an alkyl radical as defined above, e.g., [1,2-diethoxycarbonyl)ethyl]aminocarbonyl, and the like.
xe2x80x9cMono[dicarboxy]alkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(H)[Ra(C(O)OH)2] where Ra is an alkyl radical as defined above, e.g., [1,2-dicarboxy)ethyl]aminocarbonyl, and the like.
xe2x80x9cMonoalkylaminocarbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)NHRa where each Ra is independently an alkyl radical as defined above, e.g., methylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl, 3-(propylaminocarbonyl)propyl, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted arylxe2x80x9d means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
xe2x80x9cPhenylalkylidenylxe2x80x9d refers to a radical of the formula xe2x80x94ReRd where Rd is a phenyl radical and Re is a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e.g., ethylidene, propylidene, n-butylidene, and the like.
xe2x80x9cPhenylcarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)Rd where Rd is a phenyl radical.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d includes both acid and base addition salts.
xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
xe2x80x9cPharmaceutically acceptable base addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity. The amount of a compound of the invention which constitutes a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity, and includes:
(i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;
(ii) inhibiting the disease-state, i.e., arresting its development; or
(iii) relieving the disease-state, i.e., causing regression of the disease-state.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quatemized nitrogen atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
The nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as benzenamine derivatives: For example, a compound of formula (I) wherein A is xe2x80x94Oxe2x80x94, W is xe2x80x94N(R4)xe2x80x94, n is 1, R1 is 2-(carboxy)ethylcarbonyl, R2 is xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, R3 is xe2x80x94C(NH)NH2, R4 is methyl, R5 is trifluoromethyl, and R6 is hydroxy, i.e., a compound of the following formula: 
is named herein as 4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
A. Utility
The compounds of the invention are inhibitors of the serine protease, factor Xa, and are therefore useful in disease-states characterized by thrombotic activity based on factor Xa""s role in the coagulation cascade (see Background of the Invention above). A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumadin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.
In addition, the compounds of the invention are useful as in vitro and in vivo diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.
B. Testing
The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).
Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the Ki in the primary enzyme assay with the Ki for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the Ki with the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.
For further information on assays to demonstrate the activity of the compounds of the invention, see R. Lottenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., Thrombosis Research (1980), Vol. 19, pp. 579-588.
C. General Administration
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as thelan active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
Of the compounds of formula (I) as described in the Summary of the Invention, one preferred group of compounds are those compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94N(R4)xe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is xe2x80x94[C(R7)2]mxe2x80x94C(O)xe2x80x94N(R8)xe2x80x94; and R3 is xe2x80x94C(NH)NH2.
Of this group of compounds, more preferred compounds are selected from the group consisting of the following:
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(Nxe2x80x2-(3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(piperidin-4-yl)oxy-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(acetyl)piperidin-4-yl)oxy-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(aminocarbonylmethyl)-N-((Nxe2x80x2-(3-amidinophenyl)amino)carbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(1-(Nxe2x80x2-(3-amidinophenyl)aminocarbonyl)ethyl)benzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(ethoxycarbonylmethyl)-N-((Nxe2x80x2-(3-amidinophenyl)amino)carbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-((Nxe2x80x2-(3-amidinophenyl)amino)carbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(ethoxycarbonylmethyl)-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)-methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)-methylbenzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(Nxe2x80x2-(3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-N-(1-methylethyl)-N-(Nxe2x80x2-(6-benzyloxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-N-(1-methylethyl)-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine;
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(1-methylethyl)-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine; and
4-(Nxe2x80x3-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(Nxe2x80x2-(6-hydroxy-3-amidinophenyl)aminocarbonyl)methylbenzenamine.
Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94N(R4)xe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is xe2x80x94[C(R7)2]mxe2x80x94; and R3 is xe2x80x94C(NH)NH2.
Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following:
4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifuoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine;
4-(Nxe2x80x2-methylpiperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine;
4-(piperidin-4-yl)oxy-N-(2-methyl-3-amidinophenyl)prop-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine;
4-(Nxe2x80x2-(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine; and
4-(Nxe2x80x2-(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine.
Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94N(R4)xe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is xe2x80x94[C(R7)2]mxe2x80x94[C(R8)]xe2x95x90CHxe2x80x94; R3 is xe2x80x94C(NH)NH2; and R8 is hydrogen.
Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following:
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(carboxymethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-(ethoxycarbonyl)propyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(ethoxycarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-acetylpiperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(1-methylethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(methoxycarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(methoxycarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(methyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(aminocarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(aminocarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-methoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperdin-4-yl)oxy-3-methoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-((1-methylethyl)carbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1-methylethyl)carbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(methoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperdin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifuoromethyl-N-(methoxycarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-((1-methylethyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(aminocarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(methoxycarbonyl)-N-(2-(methoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(aminocarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methylsulfonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methylsulfonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1-methylethyl)carbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(ethoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(nitro)-N-(aminocarbonylmethyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(ethoxycarbonylmethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2-di(ethoxycarbonyl)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2-di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2-di(ethoxycarbonyl)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2-di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2-di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidine-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; and
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94N(R4)xe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is xe2x80x94[C(R7)2]mxe2x80x94[C(R8)]xe2x95x90CHxe2x80x94; R3 is xe2x80x94C(NH)NH2; and R8 is methyl.
Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following:
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(nitro)-N-(2-methyl-3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-N-(2-methyl-3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; and
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94N(R4)xe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is 
and R3 is xe2x80x94C(NH)NH2.
Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following:
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(acetyl)piperidin-4-yl)oxy-3-methoxy-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(ethoxycarbonylmethyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(ethoxycarbonylmethyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(carboxymethyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(ethoxycarbonylmethyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)benzyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine; and
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)benzyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine.
Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is xe2x80x94Oxe2x80x94; W is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; each m is independently 0, 1 or 2; n is 1; R2 is xe2x80x94[C(R7)2]mxe2x80x94[C(R8)]xe2x95x90CHxe2x80x94; and R3 is xe2x80x94C(NH)NH2.
Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following:
4-(tetrahydropyran-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; and
4-(thian-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Of the preferred compounds named above, the most preferred compounds are selected from the group consisting of the following:
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(carboxymethyl)-N-(3-(3-amidinophenyl)prop-2en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1 ,2-di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;
4-(Nxe2x80x2-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine, and
4-(Nxe2x80x3-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(Nxe2x80x2-(3-amidinophenyl)aminocarbonyl)methylbenzenamine.
As a matter of convenience, the following Reaction Schemes are directed to the preparation of compounds of formula (I) where W is xe2x80x94N(R4)xe2x80x94. It is also understood that in the following Reaction Schemes combinations of substituents and/or variables (e.g., R5 or R6) on the depicted formulae are permissible only if such combinations result in stable compounds.
In the following Reaction Scheme 1 depicting the preparation of compounds of formula (D), which are intermediates in the preparation of the compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; Boc is t-butoxycarbonyl; and R7 is hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (A) and formula (B) are commercially available or may be prepared according to methods known to those of ordinary skill in the art.
In general, compounds of formula (D) are prepared by first treating a compound of formula (A) in an aprotic solvent, for example, dimethylformamide, with a base, such as sodium hydride, at ambient temperature. The reaction mixture is allowed to stir at ambient temperature for 1-4 hours, preferably for 2 hours. To the reaction mixture is added a compound of formula B and the resulting reaction mixture is allowed to stir at ambient temperature for 8 to 12 hours. The compound of formula (C) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (C) so formed is then reduced under standard hydrogenation conditions (Pd/C) to form a compound of formula (D).
In the following Reaction Scheme 2 depicting the preparation of compounds of formula (H), which are intermediates in the preparation of the compounds of the invention, m is 0 to 4; and each R6 is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy). 
Compounds of formula (E) and formula (F) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (H) are prepared by first treating a compound of formula (E) in a polar solvent, such as dioxane, with an alkyl tin, such as hexamethylditin, in the presence of a catalyst, such as triphenylphosphine palladium under standard coupling reactions conditions. The compound of formula (F) is then added to the reaction mixture under similar conditions. The compound of formula (G) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (G) is then treated with a brominating agent, such as NBS, in the presence of a radical initiator, such benzoylperoxide, in an aprotic solvent, such as tetrachloromethane. The resulting solution is heated at reflux for about 10 to 15 hours, preferably for about 15 hours. The solvent is removed and the compound of formula (H) is isolated by flash chromatography.
In the following Reaction Scheme 3 depicting the preparation of compounds of formula (M), which are intermediates in the preparation of the compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 1 to 4; each R5 is hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R7 is hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (J) and formula (K) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (M) are made in a similar manner to the compounds of formula (D) as described above in Reaction Scheme 1.
In the following Reaction Scheme 4 depicting the preparation of compounds of formula (Q), which are intermediates in the preparation of the compounds of the invention, m is I to 4; each R6 is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy); and R8 is independently hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (N) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Q) are prepared by first treating a compound of formula (N) in an organic solvent, such as methylene chloride, with the appropriate Wittig reagent, such as (triphenylphosphoranylidene)acetaldehyde. The reaction mixture is stirred at reflux for 12 to 16 hours, preferably for about 16 hours. The reaction mixture is then cooled, and the compound of formula (O) is isolated from the reaction mixture by standard isolation techniques, such concentration and purification by flash chromatography.
The compound of formula (O) in an organic solvent, such as methanol, is then treated optionally with a chelating agent, such as CeCl3, and the reaction mixture was stirred for 30 minutes to 1 hour, preferaby for about 1 hour, at 0xc2x0 C. A reducing agent, such as sodium borohydride, is then added, and the resulting mixture is stirred for an additional hour at 0xc2x0 C. The mixture is concentrated and resulting residue is dissolved in an aqueous basic solution, such as aqueous NaHCO3. The compound of formula (P) is isolated from the solution by extraction, concentrated and purification by flash chromatography.
The compound of formula (P) is then treated with brominating agent, such as triphenyphosphine bromine complex, at ambient temperature. The resulting solution is stirred at 50xc2x0 C. to about 60xc2x0 C., preferably at 60xc2x0 C., for about 30 minutes to an hour, preferably for about 30 minutes. The reaction mixture is cooled to ambient temperature and concentrated. The compound of formula (Q) is isolated from the reaction mixture by trituration, filtration and concentration.
In the following Reaction Scheme 5 depicting the preparation of compounds of formula (W), intermediates in the preparation of compounds of the invention, R8 is independently hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (R) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (W) are prepared by first treating a compound of formula (R) in an aprotic solvent, such as methylene chloride, with a base, such as sodium hydride. The reaction mixture is stirred for 30 minutes to an hour, preferably for about 30 minutes, at ambient temperature. A protecting-group providing agent, such as 4-methoxybenzyl chloride is then added and the resulting reaction mixture is stirred for about 8 to 20 hours, preferably for about 16 hours, at ambient temperature. The mixture is then diluted with water and the organic layer was isolated by extraction. The compound of formula (S) was isolated form the organic layer by concentration and purification by flash chromatgraphy.
The compound of formula (S) so formed is then treated with a cyanide containing agent, such as Zn(CN)2, in the presense of a catalyst, such as Pd(PPH3)4, in an organic solvent, such as dimethylformamide. The resulting reaction mixture is stirred at around 90xc2x0 C. for 2 to 4 hours, preferably for about 3 hours, and then cooled to ambient temperature and diluted with an aqueous basic solution, such as 50% NH4OH. The compound of formula (T) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (T) is then treated in a similar manner as described above for the compounds of formula (N) to form a compound of formula (U). The compound of formula (U) is then treated in a similar manner as described above for the compounds of formula (O) to form a compound of formula (V). The compound of formula (V) is then treated in a similar manner as described for compounds of formula (P) to form the compound of formula (W).
In the following Reaction Scheme 6 depicting the preparation of compounds of formula (Y), which are intermediates of the compounds of the invention, each m is independently 0 to 4; A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; each R6 is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy); Boc is t-butoxycarbonyl; R7 is hydrogen, alkyl, aryl, or aralkyl; R8 is hydrogen, alkyl, aryl, or aralkyl; and R1 is alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, cyano). 
Compounds of formula (X) may be prepared according to methods disclosed herein are may be prepared according to methods known to those skilled in the art.
In general, the preparation of compounds of formula (Y) from compounds of formula (X) is an alkylation procedure. For example, the compound of formula (Y) in an aprotic solvent, such as DMF, in the presence of a base, such as K2CO3, is treated with an appropriate alkylating agent, such as methyl bromoacetate. The mixture is stirred at 50xc2x0 C. to about 60xc2x0 C., preferably at about 55xc2x0 C., for 4 to 8 hours, preferably for about 6 hours. After the reaction mixture is cooled to ambient temperature, the compound of formula (Y) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
In the following Reaction Scheme 6a depicting the preparation of compounds of formula (Yd), which are intermediates of compounds of the invention, A is xe2x80x94Oxe2x80x94 or N(R7)xe2x80x94; R7 is hydrogen, alkyl, aryl or aralkyl; Boc is t-butoxycarbonyl; PG is a nitrogen protecting group, e.g, trifluoromethylcarbonyl; and R5 is nitro or carboxy. 
Compounds of formula (Ya) and (B) are commercially available, or can be prepared according to methods known to those of ordinary skill in the art.
In general, compounds of formula (Yd) are prepared by first treating a compound of formula (Ya) with an appropriate protecting group providing agent, such as trifluoroacetic anhydride, in an aprotic solvent, such as methylene chloride in the presence of a base, such as triethylamine, at temperatures between 0xc2x0 C. and ambient temperature, preferably at 0xc2x0 C. The reaction mixture is stirred at this temperature for 2 to 4 hours, preferably for about 3 hours. The reaction mixture is then diluted and neutralized and the compound of formula (Yb) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (Yb) is then treated with a compound of formula (B) under Mitsunobu reaction conditions, i.e., to a mixture of the compound of formula (Yb) and the compound of formula (B) in a polar solvent, such as THF, in the presence of triphenylphosphine, is added DEAD dropwise. The reaction mixture is stirred at ambient temperature for 30 minutes to 1 hour, preferably for about 1 hour. The compound of formula (Yc) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and purification by flash chromatography.
Under basic hydrolysis conditions, such as treating the compound of formula (Yc) in a polar solvent, such as methanol and water, with a base, such as K2CO3, from ambient temperature to 100xc2x0 C., preferably at 50xc2x0 C., for 1 to 20 hours, preferably for 16 hours, the compound of formula (Yd) is formed.
In the following Reaction Scheme 6b depicting the preparation of compounds of formula (Yf), which are intermediates in the preparation of compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; R5 is alkoxycarbonyl; Boc is t-butoxycarbonyl; and R7 is hydrogen, alkyl, aryl or aralkyl. 
Compounds of formula (Ye) and (B) are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Yf) are prepared from compounds of formula (Ye) and compounds of formula (B) in a similar manner, i.e., under Mitsunobu reaction conditions, as the compounds of formula (Yc) above.
In the following Reaction Scheme 7 depicting preparation of compounds of formula (Ie), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R1 is alkylcarbonyl, alkoxycarbonyl, phenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, mono[dialkoxycarbonyl]alkylamino-carbonyl, mono[dicarboxy]alkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl; Boc is t-butoxycarbonyl; OPMB is 4-methoxybenzyloxy; R7 is hydrogen, alkyl, aryl, or aralkyl; and R8 is hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (D) and (U) may be prepared by methods disclosed herein or by methods known to those skilled in the art.
In general, compounds of formula (Ie) are prepared by first reacting a compound of formula (D) under reductive amination conditions to form a compound of formula (Z). For example, to a mixture of a compound of formula (D) and formula (Z) in a polar solvent, for example, methanol, is added a mild acid, such as acetic acid. The reaction mixture is stirred at ambient temperature for 15 minutes to 1 hour, preferably for 1 hour and then a reducing agent, such as NaCNBH3, is added and the reaction mixture is stirred at ambient temperature for 30 minutes to 1 hour, preferably for 1 hour. The reaction mixture is concentrated and the residue is taken up in a mild base, such as NaHCO3. The compound of formula (Z) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (Z) in an aprotic solvent, such as methylene chloride, is treated with an acylating agent, such as 4-chloro-4-oxobutyrate, in the presence of a base, such as pyridine, at 0xc2x0 C. The resulting solution is warmed to ambient temperature for 30 minutes to 1 hour, preferably for about 30 minutes. The compound of formula (AA) is then isolated from the reaction mixture.
The compound of formula (AA) is dissolved in an anhydrous alkanol, preferably ethanol, and then anhydrous mineral acid, preferably HCl, is added to the solution over a period of time sufficient to saturate the acid into the solution while maintaining the reaction temperatures at about xe2x88x9278xc2x0 C. After saturation is complete, the reaction vessel is sealed and the reaction mixture is allowed to warm to ambient temperature and stirred between 12 and 24 hours, preferably for about 16 hours. The solvent is removed in vacuo and the resulting residue is dissolved in fresh anhydrous alkanol, preferably ethanol, and then treated with anhydrous ammonia (gas) at temperatures from between ambient temperature and about 100xc2x0 C. from about 1 to about 48 hours, preferably at about 60xc2x0 C. and for about 2 hours. The compound of formula (Ie) is then isolated from the reaction mixture by standard isolation techniques, for example, in vacuo removal of solvent and purification by high performance liquid chromatography (HPLC). During this last step, compounds of formula (AA) any protected oxygen or nitrogen substituent is de-protected.
Alternatively, compounds of formula (D) can be reacted with compounds of formula (Q) under standard alkylating conditions to form corresponding analogs of compounds of formula (Z), which can then be reacted in a similar manner as described above for compounds of formula (Z) and formula (AA) to form compounds of the invention.
Alternatively, compounds of formula (D) can be reacted with compounds of formula (H) under standard alkylating conditions to form corresponding analogs of compounds of formula (Z), which can then be reacted in a similar manner as described above for compounds of formula (Z) and formula (AA) to form compounds of the invention.
Alternatively, compounds of formula (I) wherein R2 is xe2x80x94[C(R7)2]mxe2x80x94[C(R8)]xe2x95x90CHxe2x80x94 (as illustrated above by the compounds of formula (Ie)), can be treated under hydrogenation conditions (e.g., Pd/C) to make compounds of formula (I) wherein R2 is xe2x80x94[C(R7)2]mxe2x80x94 (saturated).
In the following Reaction Scheme 8 depicting the preparation of compounds of formula (If), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R7 is hydrogen, alkyl, aryl, or aralkyl; and R8 is hydrogen, alkyl, aryl, or aralkyl. 
Compounds of formula (Ie) are prepared according to methods disclosed.
In general, compounds of formula (If) are prepared by treating compounds of formula (Ie) under basic hydrolysis conditions, such as adding LiOH to a solution of a compound of formula (Ie) in a polar solvent, such as ethanol/water, and then stirring the reaction mixture at ambient temperature to about 100xc2x0 C., preferably at ambient temperature, for 2 to 4 hours, preferably for about 4 hours. The compound of formula (If) is isolated from the reaction mixture by standard isolation techniques, such as neutralization of the mixture by the addition of an acid, concentration and separation by HPLC.
In the following Reaction Scheme 9 depicting the preparation of compounds of formula (Ig), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; R1 is alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), mono[dialkoxycarbonyl]alkylaminocarbonyl, mono[dicarboxy]alkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; each R7 is hydrogen, alkyl, aryl, or aralkyl; R8 is hydrogen, alkyl, aryl or aralkyl, and each R9 is alkyl or aralkyl: 
Compounds of formula (If are prepared according to methods disclosed herein.
In general, compounds of formula (Ig) are prepared from compounds of formula (If) by first treating a compound of formula (If) with ethyl acetimidate in a polar solvent, such as ethanol, in the presence of a base, such as triethylamine. The reaction mixture is stirred at ambient temperature for 2 to 4 hours, preferably for about 4 hours. The mixture is then acidified and concentrated, and the compound of formula (Ig) is isolated from the concentrate by HPLC.
In the following Reaction Scheme 10 depicting the preparation of compounds of formula (Ib), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; R1 is alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), mono[dialkoxycarbonyl]alkylaminocarbonyl, mono[dicarboxy]alkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; each R7 is hydrogen, alkyl, aryl, or aralkyl; each R8 is hydrogen, alkyl, aryl, or aralkyl, and each R9 is alkyl or aralkyl: 
Compounds of formula (Ia) are prepared by methods disclosed herein.
In general, compounds of formula (Ib) are prepared by first treating a compound of formula (Ia) in a polar solvent, such as methanol, with the optionally nitrogen substituted phenyl carbamate in the presence of a base, such as triethylamine. The reaction mixture is stirred at ambient temperature for about 2 to 4 hours, preferably for about 3 hours, acidified with a mild acid and purified on HPLC to afford a compound of formula (Ib).
In the following Reaction Scheme 11 depicting the preparation of compounds of formula (Id), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; R1 is alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7), mono[dialkoxycarbonyl]alkylaminocarbonyl, mono[dicarboxy]alkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; each R7 is hydrogen, alkyl, aryl, or aralkyl; R8 is hydrogen, alkyl, aryl or aralkyl; and each R9 is alkyl or aralkyl: 
Compounds of formula (Ic) are prepared by methods disclosed herein.
In general, compounds of formula (Id) are prepared by treating a compound of formula (Ic) in an aprotic solvent, such as acetonitrile, with an acylating agent, such as acetyl chloride, at ambient temperature. The resulting mixture is stirred at ambient temperature for about 1 hour to about 4 hours, preferably for 2 hours. A base, such as LiOH in water, is added to the reaction mixture and the mixture is stirred at ambient temperature for 1 to 3 hours, preferably for 2 hours. The reaction mixture is neutralized by addition of an acid, concentrated and purified by HPLC to afford the compound of formula (Id).
In Reaction Scheme 12, which depicts the preparation compounds of formula (EE), which are intermediates in the preparation of the compounds of the invention, each R7 is independently hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (BB) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (EE) are prepared by first treating a compound of formula (BB) in an aprotic solvent, such as a mixture of dimethylformamide and acetonitrile, with a protecting group providing agent, such as benzyl bromide, in the presence of a base, such as potassium carbonate. The reaction mixture is heated at temperatures between ambient temperatures and 100xc2x0 C., preferably at about 60xc2x0 C., for about 3 to 6 hours, preferably for about 4 hours. The compound of formula (CC) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and recrystallization.
The compound of formula (CC) is then treated with a reducing agent, such as tin chloride, under standard reducing conditions to form a compound of formula (DD).
The compound of formula (DD) is then treated with an acylating agent, such as choroacetylchloride, in the presence of an anhydrous base in a polar solvent, such as acetone under a nitrogen atmosphere, to afford a compound of formula (EE).
In the following Reaction Scheme 13, depicting the preparation of compounds of formula (HH), which are intermediates in the preparation of compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4 and each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and Boc is t-butoxycarbonyl. 
Compounds of formula (B) and formula (FF) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (HH) are prepared in a similar manner as the compounds of formula (D) described above.
In the following Reaction Scheme 14 depicting the preparation of compounds of formula (Ih), which are compounds of the invention, A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4; each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; Boc is t-butoxycarbonyl; and each R7 is independently hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (EE) and formula (HH) may be prepared according to methods disclosed herein or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Ih) are prepared by first treating a compound of formula (HH) in an aprotic solvent, such as dimethyl formamide, and in the presence of a base, such as potassium carbonate, and sodium iodide with a compound of formula (EE). The reaction mixture is heated to about 80xc2x0 C. for 4 to 6 hours, preferably for about 5.5 hours. The mixture is allowed to cool and then poured onto ice water. The compound of formula (II) was isolated from the resulting slurry by standard isolation techniques, such as extraction, concentration and purification by flash chromatography.
The compound of formula (II) so formed is then treated under similar conditions as the compound of formula (AA) to form the corresponding compound of formula (Ih).
In the following Reaction Scheme 15 depicting the preparation of compounds of formula (Ii), which are compounds of the invention, X is O or NH; A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4; each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and each R7 is hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (Ih) are prepared by methods disclosed herein.
In general, the compounds of formula (Ii) are prepared by similar methods as those described above for compounds of formula (Ig).
In the following Reaction Scheme 16, depicting the preparation of compounds of formula (Ij), which are compounds of the invention, X is O or NH; A is xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94; m is 0 to 4; each R5 is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and each R7 is hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (Ii) are prepared by methods disclosed herein.
In general, compounds of formula (Ij) are prepared by standard hydrogenating conditions. Alternatively, instead of treating the above compounds of formula (AA) or formula (II) with anhydrous ammonia (gas), the compounds may be treated with a compound of the formula NH2OR9 to afford the corresponding compound of formula (I) wherein R3 is xe2x80x94C(NH)N(H)OR9.
Compounds of the invention containing an alkoxycarbonyl group may be prepared from the corresponding activated acid, such as an acid halide by techniques known to those of ordinary skill in the art.
Compounds of formula the invention containing an aminocarbonyl group, a monoalkylaminocarbonyl group, or a dialkylaminocarbonyl group may also be hydrolyzed under acidic conditions to prepare corresponding compounds of the invention containing a xe2x80x94C(O)OH group.
Compounds of the invention containing a carboxy group or an alkoxycarbonyl group may also be amidated under standard amidation conditions to form the corresponding compounds of the invention containing an aminocarbonyl group, a monoalkylaminocarbonyl group, or a dialkylaminocarbonyl group.
Compounds of the invention containing a nitro group may also be reduced under standard conditions to produce the corresponding compounds of the invention containing an amino group, which may also be treated with the appropriate alkylating agents or acylating agents to afford the corresponding compounds of the invention containing a monoalkylamino group or a dialkylamino group.
Compounds of the invention may also be further treated with the appropriate acid halide, preferably acid chloride, or with the appropriate acid anhydride or an equivalent, to yield compounds of the invention wherein R3 is xe2x80x94C(NH)N(H)C(O)R7 where R7 is hydrogen, alkyl, aryl or aralkyl.
Alternatively, compounds of the invention may further be treated with a compound of formula Clxe2x80x94C(O)xe2x80x94OR9 or its functional equivalent to yield compounds of the invention where R3 is xe2x80x94C(NH)N(H)C(O)OR9.
Alternatively, compounds of the invention may also be further treated with compounds of the formula R9xe2x80x94S(O)2-imidazole (where R9 is defined above in the Summary of the Invention) in a polar solvent, such as methylene chloride, at ambient temperature to afford compounds of the invention where R9 is xe2x80x94C(NH)N(H)S(O)2R9 where R9 is defined above in the Summary of the Invention.
Alternatively, compounds of formula the invention may be further treated with an appropriately Nxe2x80x94R7-substituted phenylcarbamate in a polar solvent, preferably methylene chloride, at ambient temperature, for about 6 to 24 hours, preferably for about 12 hours, to afford compounds of the invention where R3 is xe2x80x94C(NH)N(H)C(O)N(H)R7 where R7 is defined above in the Summary of the Invention.
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques.